Although family history represents one of the greatest risk factors for drug addiction, the genetic and epigenetic basis for such illnesses remains poorly understood. A growing body of evidence indicates that many drugs of abuse, such as amphetamine or cocaine, induce alterations in gene expression which appear transiently after drug exposure. However, no study has been conducted so far elucidating the effects that repeated drug administration can generate in subsequent generations. Because drug addiction is a highly heritable illness, it is crucial to examine whether altered gene expressions induced by drugs of abuse are likewise transmittable to future generations. This would involve stable, epigenetic modifications, which persist in offspring and affect addiction vulnerability. The central goal of this grant proposal is to investigate the trans-generational effects of amphetamine at the dopaminergic synapses. Particularly, we investigate the transgenerational effects amphetamine causes at the dopamine transporter and dopamine receptors because these proteins are important targets of drugs of abuse such amphetamine and cocaine, and are central key players of the reward pathway. We hypothesize that by triggering epigenetic changes in the genes and pathways responsible for mediating the brain?s response to amphetamine, behavioral and physiological changes associated with this psychostimulant are passed down to subsequent generations. Our proposal investigate the epigenetic changes induced by amphetamine that are passed through subsequent generations (Aim 2) and includes a thorough functional investigation of how amphetamine alters the activity of key players of the dopaminergic system in progeny (Aim 1). Importantly, as epigenetic mechanisms are dynamic and reversible, we also designed a plan in which we test if pharmacological intervention, with specific drugs that inhibit epigenetic modifications, prevents the transgenerational effects induced by amphetamine (Aim 3).